Sex differences in the neural correlates underlying impairments in response inhibition and salience attribution in cocaine addiction

神经系统中的性别差异与可卡因成瘾的反应抑制和显着性归因的潜在损伤相关

• 批准号: 10358597
• 负责人: Rita Z Goldstein
• 金额: $ 68.93万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358597
• 关键词: Abstinence; Address; Adverse effects; Anatomy; Behavioral; Chronic; Classification; Clinical; Clinical Trials; Cocaine Dependence; Cocaine use disorder; Cognitive; Corpus striatum structure; Cues; Data; Data Set; Development; Dopamine; Drug Addiction; Drug usage; Early treatment; Emotional; Epidemic; Female; Functional Magnetic Resonance Imaging; Future; Gender; Goals; Gonadal Steroid Hormones; Hormonal; Impairment; Impulsivity; Individual; Informal Social Control; Intervention; Intoxication; Luteal Phase; Machine Learning; Magnetic Resonance Imaging; Maps; Measures; Menstrual cycle; Modeling; Monitor; Neurosciences; Opiate Addiction; Participant; Pattern; Performance; Pharmaceutical Preparations; Phase; Population; Prefrontal Cortex; Proxy; Psychological reinforcement; Public Health; Recovery; Recurrent disease; Relapse; Research; Resources; Rest; Rewards; Role; Scanning; Series; Severities; Sex Differences; Signal Transduction; Specificity; Stimulant; Stimulus; Symptoms; Testing; Withdrawal; Woman; addiction; base; blood oxygen level dependent; cocaine use; cost; craving; cue reactivity; design; diagnostic criteria; drug of abuse; gray matter; imaging modality; imaging study; machine learning algorithm; male; men; neural correlate; neural network; neurobiological mechanism; neuroimaging; neurotransmission; non-drug; opioid use disorder; precision medicine; psychostimulant; recruit; relating to nervous system; response; reward processing; sex; sexual dimorphism; stress reactivity; symptomatology; systematic review; tool; treatment strategy

National studies show that drug use rates have increased in the last decade among women, comprising a major public health concern in the US. However, women are greatly underrepresented in neuroimaging studies, and the paucity of studies that explicitly target sex comparisons in addicted populations contributes to a gap in the study of the sex specific neurobiological mechanisms underlying drug addiction. Over the last decade, in a series of magnetic resonance imaging (MRI) studies (conducted with previous support including R01DA023579, R01DA020949), we have thoroughly mapped the clinical symptoms of cocaine addiction to the neural networks underlying impairments in Response Inhibition and Salience Attribution (iRISA). This model proposes that the drug assumes heightened salience at the expense of non-drug related reinforcement as associated with abnormalities in reward processing and concomitant decreases in inhibitory control, together increasing addiction severity (including craving, a proxy of relapse) in susceptible individuals. The iRISA model highlights the role of the dopaminergically innervated prefrontal cortex (PFC) and its connections to mesolimbic and striatal subcortical regions as assessed functionally and structurally. However, the majority of this neuroimaging research has been accomplished in male individuals with cocaine use disorders (iCUD). In the current project we aim to expand the reach of iRISA by comparing equal numbers of male to female iCUD; to test this model’s generalizability (vs. drug specificity effects), we will also include individuals with opioid use disorder (iOUD). We will conduct functional MRI during reward processing, inhibitory control and cue-reactivity tasks, and, to inspect generalizability of results beyond task-related activations, during resting-state. Beyond functional activations and connectivity, anatomical scans will assess the underlying gray matter integrity. Across all aims, healthy controls will be included to establish norms. We hypothesize female iCUD to differ from male iCUD, or female controls, in a pattern indicative of enhanced vulnerability to iRISA inclusive of compensatory PFC activations and abnormalities in structural measures; iCUD vs. iOUD comparisons will be exploratory. The novelty of this proposal is further enhanced by an exploratory aim to compare, in a within- subjects design, menstrual cycle (and hormonal) effects and by developing sophisticated machine-learning algorithms to incorporate data from all imaging modalities to yield an automated group classification and addiction severity (including craving) prediction tool. Considering that the majority of research in addiction occurs in males, clarification of the sex differences in the neural underpinnings of iRISA could reinforce the importance of studying both genders and suggest that different treatment strategies may be effective in women (potentially of most impact when timed vis-à-vis menstrual cycle), contributing to the development of tailored (gender-based) treatment options. Including equal numbers of women and men would advance basic studies of drug addiction and ultimately save resources by minimizing cost and adverse effects in future clinical trials.

国家研究表明，过去十年来，女性吸毒率有所上升，其中包括 美国主要的公共卫生问题。然而，女性在神经影像学领域的代表性严重不足 研究，而且缺乏明确针对成瘾人群性别比较的研究，导致 药物成瘾背后的性别特异性神经生物学机制的研究存在空白。过去的 十年来，在一系列磁共振成像（MRI）研究中（在先前的支持下进行，包括 R01DA023579，R01DA020949），我们已经将可卡因成瘾的临床症状彻底映射到 神经网络潜在的反应抑制和显着归因（iRISA）损伤。这个型号 提出该药物以牺牲非药物相关的强化为代价而呈现出更高的显着性，因为 与奖励处理异常和随之而来的抑制控制减少有关 易感人群的成瘾严重程度（包括渴望，复吸的指标）增加。 iRISA 模型 强调多巴胺能神经支配的前额皮质 (PFC) 的作用及其与中脑边缘的联系 和纹状体皮层下区域的功能和结构评估。然而，这其中的大多数 神经影像学研究已在患有可卡因使用障碍 (iCUD) 的男性个体中完成。在 目前的项目我们的目标是通过比较同等数量的男性和女性 iCUD 来扩大 iRISA 的覆盖范围；到 测试该模型的普遍性（与药物特异性效应），我们还将包括使用阿片类药物的个体 紊乱（iOUD）。我们将在奖励处理、抑制控制和提示反应期间进行功能性 MRI 任务，并在静息状态下检查任务相关激活之外的结果的普遍性。超过 功能激活和连接性，解剖扫描将评估潜在灰质的完整性。 在所有目标中，都将包括健康控制以建立规范。我们假设女性 iCUD 有所不同 来自男性 iCUD 或女性对照，其模式表明 iRISA 的脆弱性增强，包括 补偿性 PFC 激活和结构措施异常； iCUD 与 iOUD 的比较将是 探索性的。该提案的新颖性通过探索性目的进行比较进一步增强，在 受试者设计、月经周期（和荷尔蒙）影响以及开发复杂的机器学习 整合来自所有成像模式的数据以产生自动组分类的算法 成瘾严重程度（包括渴望）预测工具。考虑到大多数关于成瘾的研究 发生在男性中，澄清 iRISA 神经基础的性别差异可以加强 研究两种性别的重要性，并表明不同的治疗策略可能对女性有效 （当时间与月经周期相关时可能产生最大影响），有助于开发定制的 （基于性别的）治疗方案。包括同等数量的女性和男性将促进基础研究 药物成瘾的研究，并通过在未来的临床试验中最大限度地减少成本和不良反应来最终节省资源。